Practice Patterns of Physician Treatment for Pediatric Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a rare disease in children for which pediatric evidence-based guidelines are lacking. We designed an anonymous survey for practicing pediatric oncologists and bone marrow transplantation (BMT) physicians to assess their willingness to recommend BMT for a patient with CML based on various clinical scenarios. A total of 274 physicians responded to the survey (13.4% response rate). Nearly all pediatric oncologists and BMT physicians recommended against BMT at time of diagnosis of CML in the chronic phase, with only 8.0% and 1.9% recommending BMT if a matched sibling donor (MSD) and a matched unrelated donor (MUD), respectively, was available. Similarly, after a first poor response to tyrosine kinase inhibitor (TKI) therapy or hematologic relapse, physicians continued to recommend against BMT (39.5% and 23.3% recommended BMT in patients with a matched sibling donor and matched unrelated donor, respectively). However, 81.7% and 69.8% of respondents would recommend BMT after 2 hematologic relapses on TKI therapy, if an MSD and an MUD, respectively, were available. In addition, there was great interest in developing a clinical trial evaluating the safety and efficacy of stopping TKIs in children with CML who achieve and maintain a deep molecular response, with 86.7% of respondents stating they would offer such a trial to their pediatric patients. This survey highlights the need for evidence-based, pediatric-specific guidelines for the management of children and adolescents with CML.     

Imatinib mesylate--gold standards and silver linings

Imatinib mesylate represents the first of a new generation of molecularly targeted therapies engineered to disrupt signal transduction pathways. It is a tyrosine kinase inhibitor with relatively selective activity against the Abelson (ABL) proto-oncogene, platelet-derived growth factor receptor, and c-KIT receptor. Deregulated tyrosine kinase activity has been implicated as a central pathogenic event in a number of human malignancies, most notably chronic myeloid leukemia. In this myeloproliferative disorder the t(9;22) reciprocal translocation results in the generation of a novel fusion oncoprotein, BCR-ABL, with constitutive tyrosine kinase activity. Imatinib inhibits this activity, inducing remarkable rates of hematological and cytogenetic remission in excess of those seen with alternative medical therapies. Following a large phase III study comparing its efficacy with the combination of interferon alpha and low-dose cytarabine, it has emerged as the current gold standard therapy for patients with chronic-phase disease without a potential bone marrow donor and those considered unsuitable for bone marrow transplantation. Its integration into the management of those patients who might be considered for transplantation, which has historically been considered the only potentially curative approach, remains a major challenge. The increasing recognition and subsequent molecular characterization of resistance mechanisms has reinforced the need to exercise caution against deferring a proven curative therapy in favor of a treatment approach that is still investigational, with the spectre of increased numbers of patients progressing to sudden-onset blast crisis remaining the potential dark cloud in the silver lining for imatinib.     

第一代与第二代TKI治疗慢性粒细胞白血病的疗效

目的 评估第一代与第二代酪氨酸激酶抑制剂（TKI）治疗慢性粒细胞白血病（CML）的临床疗效及安全性。方法 回顾性分析2008年10月~2019年5月在我院接受治疗的324例确诊为CML慢性期患者的临床资料,根据治疗方法将其分为A、B两组,A组（267例）患者接受第一代TKI药物治疗,B组（57例）接受第二代TKI药物治疗,共57例,比较两组临床疗效、5年和10年总生存（OS）率、无进展生存（PFS）率及不良反应情况。结果 ①截止到随访结束,A组共75例患者换用第二代TKI治疗,其3、6、9、12个月达CCyR率分别为49.33%、72.00%、80.00%、88.00%,MMR率分别为62.67%、78.67%、86.67%、88.00%。②治疗3个月,两组CHR率、MMR率比较,差异无统计学意义（P＞0.05）;B组CCyR率高于A组,差异有统计学意义（P＜0.05）;治疗6个月,B组CHR率、CCyR率及MMR率均高于A组,差异有统计学意义（P＜0.05）;治疗9、12个月,两组CHR率均达100.00%,B组CCyR率及MMR率高于A组,差异有统计学意义（P＜0.05）。③A、B两组均无10年无进展生存患者,A组患者5年OS率、5年PFS率、10年OS率分别为86.14%、72.28%、80.52%,均低于B组的96.49%、89.47%、92.98%,差异有统计学意义（P＜0.05）。④两组患者均有不良反应出现,且多合并多种不良反应,其中A组不良反应发生率为27.34%,低于B组的10.53%,差异有统计学意义（P＜0.05）。结论 第二代TKI治疗慢性粒细胞白血病临床疗效更好,其完全细胞遗传学缓解率、主要分子生物学缓解率高,不良反应少,安全性高,在经济允许的情况下,应建议患者优先选择第二代TKI治疗。     

Proposal of a morphologic bone marrow response score for imatinib mesylate treatment in chronic myelogenous leukemia

Cytogenetic and molecular analyses are essential disease-monitoring parameters in chronic myelogenous leukemia (CML) treated with imatinib. However, a bone marrow morphologic response has not been defined. We reviewed bone marrow histology and cytology of 39 imatinib-treated patients with CML over 49 weeks and introduced a morphologic response score. A significant positive correlation with a complete cytogenetic response was shown for absence of dry tap (P = .04) and abnormal megakaryocytes (P < 0.001), normalization of cellularity (P = .001) and reduction of fibrosis (P = .01), myelopoiesis:erythropoiesis index (P = .001), blast (P = .001) and basophil count (P < 0.001). The morphologic score integrating these parameters showed an early and late correlation with cytogenetic response. In conclusion, morphologic criteria for complete cytogenetic response in patients with CML treated with imatinib can be defined. Persistent high-level morphologic abnormalities herald early on a high likelihood to fail treatment and call for more intense or alternative therapy.     

慢性粒细胞白血病患者中西医结合治疗前后舌微循环及骨髓超微结构变化

目的:观察45例慢性粒细胞白血病(CML)患者中西医结合治疗前后的舌尖微循环及骨髓超微结构变化.方法:对45例复方黄黛片联合羟基脲治疗CML患者治疗前后的舌尖微循环及骨髓组织病理、超微结构进行对比观察.结果:CML患者治疗前舌尖微循环超微结构变化包括微血管扩张、内皮肿胀、微血管数量增多; 骨髓组织病理表现为中晚幼粒细胞...     

In vitro inhibitory effects of imatinib mesylate on stromal cells and hematopoietic progenitors from bone marrow

Imatinib mesylate (IM) is used to treat chronic myeloid leukemia (CML) because it selectively inhibits tyrosine kinase, which is a hallmark of CML oncogenesis. Recent studies have shown that IM inhibits the growth of several non-malignant hematopoietic and fibroblast cells from bone marrow (BM). The aim of the present study was to evaluate the effects of IM on stromal and hematopoietic progenitor cells, specifically in the colony-forming units of granulocyte/macrophage (CFU-GM), using BM cultures from 108 1.5- to 2-month-old healthy Swiss mice. The results showed that low concentrations of IM (1.25 µM) reduced the growth of CFU-GM in clonogenic assays. In culture assays with stromal cells, fibroblast proliferation and α-SMA expression by immunocytochemistry analysis were also reduced in a concentration-dependent manner, with a survival rate of approximately 50% with a dose of 2.5 µM. Cell viability and morphology were analyzed using MTT and staining with acrydine orange/ethidium bromide. Most cells were found to be viable after treatment with 5 µM IM, although there was gradual growth inhibition of fibroblastic cells while the number of round cells (macrophage-like cells) increased. At higher concentrations (15 µM), the majority of cells were apoptotic and cell growth ceased completely. Oil red staining revealed the presence of adipocytes only in untreated cells (control). Cell cycle analysis of stromal cells by flow cytometry showed a blockade at the G₀/G₁ phases in groups treated with 5-15 µM. These results suggest that IM differentially inhibits the survival of different types of BM cells since toxic effects were achieved.     

BCR-ABL kinase domain mutations in tyrosine kinase inhibitors-naïve and -exposed Southeast Asian chronic myeloid leukemia patients

BCR-ABL kinase domain (KD) mutation is the main mechanism associated with resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) patients. This study targeted a large cohort of CML (n = 171) comprising 80 naïve CML cases without prior TKI exposure as well as 91 cases undergoing 1st generation (imatinib) and/or 2nd generation (nilotinib/dasatinib) TKI therapy. KD mutations were analyzed by denaturing high performance liquid chromatography followed by direct sequencing. Twenty-one types of mutations were found in 37 patients including 13 known mutations and 8 previously unidentified mutations. Thirty cases had a single mutation while 7 cases had multiple mutations. Twenty-three percent of patients receiving first-line imatinib, 69% of imatinib-resistant patients receiving 2nd generation TKI, and 75% of advanced phase patients treated with front-line 2nd generation TKI had KD mutations. Interestingly, 9% of TKI-naïve CML cases were also discovered to carry the KD mutations including 5 novel variants. Patients who received hydroxyurea had a 2-fold increase in KD mutations as compared to newly diagnosed patients but they still had a lower mutation frequency than TKI-exposed cases. Mutations in the naïve cases were mainly localized in the C-helix domain and SH3 contact site whereas in exposed cases predominantly in the drug contact site, P-loop, and catalytic domain. T315I resistant mutation was identified only in TKI-exposed cases. In conclusion, several known and novel BCR-ABL KD mutations were discovered in the TKI-naïve and -exposed Southeast Asian CML patients, supporting the concept that naturally occurring KD mutations were present in leukemic cells prior to drug exposure. T315I resistant mutation was completely undetectable in this naïve Southeast Asian cohort; its incidence, however, increases with drug exposure.     

Survivin isoform expression patterns in CML patients correlate with resistance to imatinib and progression, but do not trigger cytolytic responses

Tyrosine-kinase inhibitors are very effective in patients with CML, but in most cases the disease relapses after their discontinuation. As a result, novel approaches should be considered, such as anti-survivin treatment or anti-survivin-based immunotherapy. To gain insight into the roles of survivin isoform expression and specific CD8(+) T cells in CML, we investigated 51 patients at different stages, both at diagnosis and during treatment. We demonstrated that (i) patients at advanced-stage displayed an increased expression of the standard-survivin form along with a significant decrease of survivin-2B and -ΔEx3 levels, (ii) patients in chronic phase with higher expression of the standard-survivin exhibited a 3.5-fold increased probability not to achieve an optimal response to imatinib (p=0.048), (iii) responders displayed a significant up-regulation of all survivin isoforms in bone marrow, and (iv) anti-survivin CD8(+) T cells were undetectable both at diagnosis and during treatment. Accordingly, our results question the validity of immunotherapeutic approaches targeting survivin in CML.     

Myeloid dysplasia (MD): a hematological disorder preceding acute and chronic myeloid leukemia

Summary Light- and electron microscopic appearances of core biopsies of the bone marrow in 27 selected patients out of about 195 cases with a clinically suspected preleukemic syndrome. The correct diagnosis of preleukemia was established retrospectively by sequential biopsies of the iliac crest or autopsy in those patients who developed overt leukemia in periods ranging from 2 to 36 months. As a final diagnosis chronic myelogenous leukemia (CML) was established in 10, with accompanying blast crisis in 6 and acute non-lymphocytic leukemia (ANLL) in 11 cases. Histomorphology of the resin embedded cores of bone marrow showed hypercellularity in 21 specimens, a hypocellular marrow in 5 and a normal bone marrow in 1 case. There was also a conspicuous macrocytic or megaloblastoid maturation of erythropoiesis with frequent sideroblasts. Ultrastructural abnormalities included atypical nuclear clefts, dense iron deposits in the mitochondrial matrix and an increase of ferritin uptake. Neutrophilic granulopoiesis showed a shift to the left and often a remarkable aberration of nuclear segmentation consistent with a pseudo-Pelger-Huët anomaly. Electron microscopy displayed atypias of granulogenesis in comparison with maturation and segmentation of the nuclei, abnormal nuclear loops and blebs and very conspicuous nuclear fibrillar appendages (so called Nebenkerne). There was also an increase in eosinophilic granulocytes, monocytic elements, edema and a remarkable perivascular plasmacytosis of the myeloid stroma. Our results suggest that characteristic morphological features of the bone marrow exist before onset of overt, acute and chronic leukemia. These alterations are identical in CML and ANLL and are the morphological substrate of a maturation defect of hematopoiesis which precedes the establishment of the leukemic clone. The clinical term preleukemia should be replaced by myeloid dysplasia (MD), thus indicating transformation into overt leukemia in only a certain proportion of patients (only 27 of 195 clinically suspected patients who displayed an identical histopathology of MD in the bone marrow in 93 cases to date) and has to include ANLL as well as CML.Supported by the Deutsche Forschungsgemeinschaft (grant Ge 121/19)